Prodrugging fungicidal amphotericin B significantly decreases its toxic effects

Amphotericin B (AmB) is one of the most effective antifungal drugs, with a strong, dose-dependent activity against most Candida and Aspergillus species responsible for life-threatening infections. However, AmB is severely toxic, which hinders its broad use. In this proof-of-concept study, we demonstrate that prodrugging AmB considerably decreases AmB toxicity without affecting its fungicidal activity. For this purpose, we modified the AmB structure by attaching a designer phosphate promoiety, thereby switching off its mode of action and preventing its toxic effects. The original fungicidal activity of AmB was then restored upon prodrug activation by host plasma enzymes. These AmB prodrugs showed a safer toxicity profile than commercial AmB deoxycholate in Candida and Aspergillus species and significantly prolonged larval survival of infected Galleria mellonella larvae. Based on these findings, prodrugging toxic antifungals may be a viable strategy for broadening the antifungal arsenal, opening up opportunities for targeted prodrug design. [Display omitted] •Fungal infections represent a serious threat, especially for immunocompromised patients.•Amphotericin B (AmB) has a dose-dependent broad-spectrum antifungal activity but its broad use is hindered by high nephrotoxicity.•Prodrugging of AmB significantly suppresses its toxic effects. The original activity of AmB is restored in the host by the action of host enzymes.•AmB prodrugs show safer toxicity profile than AmB deoxycholate and significantly prolonged larval survival of infected G. mellonella larvae.